6Q3Y

Crystal structure of the first bromodomain of human BRD4 in complex with the inhibitor 16i


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.176 
  • R-Value Work: 0.142 
  • R-Value Observed: 0.143 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity.

Watts, E.Heidenreich, D.Tucker, E.Raab, M.Strebhardt, K.Chesler, L.Knapp, S.Bellenie, B.Hoelder, S.

(2019) J Med Chem 62: 2618-2637

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01947
  • Primary Citation of Related Structures:  
    6Q3Y, 6Q3Z

  • PubMed Abstract: 

    Concomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in a significant fraction of high-risk neuroblastoma patients, mutation of ALK and amplification of MYCN. Starting from known dual polo-like kinase (PLK)-1-BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with a dual ALK-BRD4 profile. These efforts led to compound ( R)-2-((2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-7-ethyl-5-methyl-8-((4-methylthiophen-2-yl)methyl)-7,8-dihydropteridin-6(5 H)-one (16k) demonstrating improved ALK activity and significantly reduced PLK-1 activity, while maintaining BRD4 activity and overall kinome selectivity. We demonstrate the compounds' on-target engagement with ALK and BRD4 in cells as well as favorable broad kinase and bromodomain selectivity.


  • Organizational Affiliation

    Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SM2 5NG , U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4
A, B
127Homo sapiensMutation(s): 0 
Gene Names: BRD4HUNK1
UniProt & NIH Common Fund Data Resources
Find proteins for O60885 (Homo sapiens)
Explore O60885 
Go to UniProtKB:  O60885
PHAROS:  O60885
GTEx:  ENSG00000141867 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60885
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HG5
Query on HG5

Download Ideal Coordinates CCD File 
D [auth A],
L [auth B]
(7~{R})-2-[[2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl]amino]-7-ethyl-5-methyl-8-(phenylmethyl)-7~{H}-pteridin-6-one
C30 H38 N6 O2
TWABWUVZWXSPTC-RUZDIDTESA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A]
E [auth A]
F [auth A]
G [auth A]
H [auth A]
C [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth B],
J [auth B],
K [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
HG5 Binding MOAD:  6Q3Y Kd: 54 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.176 
  • R-Value Work: 0.142 
  • R-Value Observed: 0.143 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 30.34α = 83.93
b = 39.53β = 75.64
c = 56.03γ = 89.75
Software Package:
Software NamePurpose
REFMACrefinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-03-06
    Type: Initial release
  • Version 1.1: 2019-03-27
    Changes: Data collection, Database references
  • Version 1.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description